Review Article Management of the trigeminocardiac : Facts and own experience

Belachew Arasho1,4, Nora Sandu2, Toma Spiriev1, Hemanshu Prabhakar3, Bernhard Schaller1

1Departments of Neurosurgery, University of Paris, France, 2University of Lausanne, Switzerland, 3Neuroanesthesiology, Neurosciences Center, All India Institute of Medical Sciences, New Delhi, India, 4Department of Neurology, Addis Ababa University, Ethiopia

Abstract

The trigeminocardiac reflex (TCR) is defined as the sudden onset of parasympathetic dysrhythmia, sympathetic hypotension, apnea, or gastric hyper-motility during stimulation of any of the sensory branches of the . The proposed mechanism for the development of TCR is—the sensory nerve endings of the trigeminal nerve send neuronal signals via the Gasserian ganglion to the sensory nucleus of the trigeminal nerve, forming the afferent pathway of the reflex arc. It has been demonstrated that the TCR may occur with mechanical stimulation of all the branches of the trigeminal nerve anywhere along its course (central or peripheral). The reaction subsides with cessation of the stimulus. But, some patients may develop severe , asystole, and arterial hypotension which require intervention. The risk factors already known to increase the incidence of TCR include: Hypercapnia; hypoxemia; light general anesthesia; age (more pronounced in children); the nature of the provoking stimulus (stimulus strength Address for correspondence: and duration); and drugs: Potent narcotic agents (sufentanil and alfentanil); beta- Dr. Bernhard Schaller, blockers; and calcium channel blockers. Because of the lack of full understanding Department of Neurosurgery, of the TCR physiology, the current treatment options for patients with TCR include: University of Paris, France. (i) risk factor identification and modification; (ii) prophylactic measures; and (iii) E-mail: [email protected] administration of vagolytic agents or sympathomimetics.

Key words: , cardiac reflex, oculocardiac reflex, skull base surgery, DOI: 10.4103/0028-3886.55577 treatment, trigemino

Introduction reflex occurs with stimulation of the intracranial portion of the trigeminal nerve.[1] Again Schaller was the first who The trigeminal nerve is the largest of the , subsummarized all these under the term TCR.[2,9] and it provides sensory supply to the face, scalp, and Since then, there has been much discussion about the reflex mucosa of the nose and mouth.[1-3] Stimulation of the itself and the prophylaxis and treatment of the TCR when trigeminal receptors that innervate the nose and nasal it occurs during intracranial or extracranial procedures. passages is thought to provide an important stimulus for But until now, there exists no clear recommendations the initiation of the trigeminorespiratory reflex and cardiac how to treat the TCR. So, the aim of the present work is to arrhythmias which could arise with it. This has been update knowledge about currently available treatment studied in animals and known for more than a century,[4-6] options for patients with TCR. and is now considered as the trigeminocardiac reflex th (TCR). In the early 20 century, this TCR has gained much Definition and Pathophysiology of the clinical attention, in the form of the oculocardiac reflex (OCR) which is the cardiac response (mainly bradycardia) Trigeminocardiac Reflex associated with stimulation of the ophthalmic division of the trigeminal nerve during ocular surgeries.[7,8] Then, The TCR is defined as the sudden onset of parasympathetic Schaller, for the first time, demonstrated that a similar dysrhythmia, sympathetic hypotension, apnea, or

Neurology India | Jul-Aug 2009 | Vol 57 | Issue 4 375 Arasho, et al.: Trigeminocardiac reflex gastric hyper-motility during stimulation of any of the with the same definition used as in his prior study, i.e., sensory branches of the trigeminal nerve.[1] The proposed heart rate less than 60 beats per minute and MABP 20% mechanism for the development of the TCR is that the lower than the baseline.[20] TCR was also reported during sensory nerve endings of the trigeminal nerve send transsphenoidal surgery for pituitary adenoma.[9,19,21] neuronal signals via the Gasserian ganglion to the sensory Among 117 patients who underwent transsphenoidal nucleus of the trigeminal nerve, forming the afferent surgery for pituitary adenoma, 10% developed a TCR pathway of the reflex arc.[1,2] This afferent pathway during the surgical procedure.[19] Peripheral stimulation continues along the short internuncial nerve fibres in the of the naso-pharynx may also lead to TCR.[9] to connect with the efferent pathway in the motor nucleus of the . Several lines Risk Factors for Occurrence of the of experimental evidence demonstrate that trigeminally Trigeminocardiac Reflex induced cardiovascular reflexes could be mediated initially in the trigeminal nucleus caudalis and subsequently in the As there is a lack of detailed knowledge of the physiology parabrachial nucleus, the rostral ventrolateral medulla of the TCR and since we cannot treat in whole the TCR, oblongata, the dorsal medullary reticular field, and the the risk factors gain increased importance. The risk [3,10,11] paratrigeminal nucleus in animal models. factors already known to increase the incidence of TCR include: (i) hypercapnia; (ii) hypoxemia; (iii) light general The TCR occurs during both, the peripheral and the anesthesia; (iv) age (more pronounced in children); (v) the central manipulations of the trigeminal nerve. The OCR, nature of the provoking stimulus (stimulus strength and which is a subform of the TCR, has long been reported duration); and (vi) drugs. Drugs known to increase the [7,8,12] in patients with ocular surgeries and manipulations. TCR include: (i) potent narcotic agents (sufentanil and In 1999, Schaller et al., for the first time, reported the alfentanil);[22,23] (ii) beta-blockers; and (iii) calcium channel occurrence of the TCR in skull base and neurological blockers.[24] Narcotics may augment vagal tone through [1] surgeries. The underlying responsible mechanism is their inhibitory action on the sympathetic nervous not yet fully understood, but is believed to be the same system.[1,25-27] Beta-blockers reduce the sympathetic as the OCR reported earlier on, i.e., activation of the response of the heart and by so doing, augment the [2] central or intracranial portions of the trigeminal nerve. vagal cardiac response resulting in bradycardia. Calcium channel blockers result in peripheral arterial smooth Epidemiology of the Trigeminocardiac Reflex muscle relaxation and vasodilatation causing reduction in blood pressure. In patients undergoing trigeminal It has been demonstrated that the TCR may occur manipulations, this worsens the vagal effect that occurs with manipulation of all the branches of the trigeminal in some patients. nerve anywhere along its (intracranial or extracranial) course.[7,8,12- 16] The OCR, which is a subvariant of the TCR, Case Report and studied far earlier, was said to occur in up to 67% of the patients operated for strabismus,[17] but a lot of authors A 60-year-old male patient with a diagnosis of right-sided only studied the heart rate and a reduction in heart rate vestibular schwannoma underwent tumor resection by 10% or more was taken as a positive OCR, so that the via a retrosigmoid (suboccipital approach) approach. real incidence may be substantially smaller. According His medical history was significant for long standing to Schaller’s experience, the TCR occurs in 10-18% of the hypertension for which he is taking irbesartan (an patients.[1,18-20] In a retrospective review of 125 patients angiotensin receptor blocker) and a 14-pack-year history operated for tumors of the cerebello-pontine angle, of smoking. Otherwise, he has no history of diabetes, Schaller et al. noticed the occurrence of the TCR in 11% of cardiac problems, and was not on beta blockers or calcium the operated patients.[4] Three of the patients in this series channel blockers. His baseline MABP was 73.2 mm Hg developed asystole which lasted from 30- 70 seconds.[1] and heart rate was 65 beats per minute. Two hours after In contrast to the studies on OCR, Schaller take into skin incision, his MABP dropped to 43.3 mm Hg (40.8% consideration the heart rate and blood pressure into drop from the baseline) and concomitantly, his heart account and defined TCR as heart rate less than 60 beats rate dropped to 40 beats per minute (38% drop from per minute and mean arterial blood pressure (MABP) 20% the baseline). Then, the procedure was discontinued; lower than the baseline.[1] he was given epinephrine and crystalloid fluids. After five minutes, his MABP and heart rate stabilized and the In another study, Schaller also showed the occurrence surgical procedure was carried out successfully to the of TCR during microvascular decompression of the end without any further episodes of TCR. His oxygen trigeminal nerve for trigeminal neuralgia.[20] In this saturation was 100% and no hypercarbia occurred. The review on 28 patients, the incidence of TCR was 18% postoperative course was uneventful.

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Clinical significance of the trigeminocardiac reflex occurrence of postoperative ipsilateral tinnitus: The and why it should be treated overall incidence of postoperative ipsilateral tinnitus Most authors recognized that the TCR is a transient was 22%. A total of 60% patients in the TCR subgroup response to the trigeminal nerve manipulation in and only 17% of in the nonTCR subgroup experienced its extra or intracranial course which subsides with ipsilateral tinnitus postoperatively.[32] These studies cessation of the stimulus. But, in the most serious forms show that there is a tendency for increased complication of severe bradycardia and asystole, administration of rates in patients who developed TCR compared to those vagolytic agents is warranted in addition to cessation without it, again stressing the importance of looking it of the stimulus. Rath et al. reported a case of asystole carefully during neurosurgical and especially skull base occuring in a patient who was undergoing percutaneous surgical procedures. retrogasserian glycerol rhizolysis for trigeminal neuralgia.[28] Immediately after injection of anhydrous Management of the Trigeminocardiac Reflex glycerol, the patient became unresponsive, the pulse became impalpable, blood pressure unrecordable, the There has been a lot of discussion about the best and ECG showed asystole, and had a respiratory arrest. more effective treatment for TCR.[33-42] It is beyond the The patient regained consciousness and heart rate and scope of this manuscript to discuss all these influences. blood pressure returned to normal after 30 seconds with Without any doubt, application of atropine is not the oxygen and IV atropine.[28] Prabhakar et al. also reported only modality of treatment, based on physiological a case of sudden asystole without prior bradycardia knowledge of the reflex and based on clinical experience. which occurred during surgery for cerebellopontine To the authors opinion, the first and the most important angle tumor.[29] This case was just managed by cessation “management option” for the TCR is to be aware of of the manipulation without administration of vagolytic its potential danger and minimize any mechanical agents.[30] Fayol et al. also reported a five-year-old boy stimulation of the nerve. who was operated for strabismus and possibly died due to OCR which developed on underlying myocarditis. [30] According to the clinical experience on this topic, the These cases demonstrate the (clinical) importance of the management of patients with TCR can be classified into TCR which may range from mild bradycardia which the following categories which are illustrated in the responds to simple cessation of the stimulus to asystole flow-chart [Figure 1]: and severe bradycardia requiring additional intervention with vagolytics. In some rare but serious cases, it may 1. Risk factor identification and modification. lead to death if not detected early and appropriate 2. Prophylactic treatment with either vagolytic agents measures taken. or peripheral nerve blocks in case of peripheral In addition, hypotension which occurs during the TCR may lead to myocardial and cerebral infarction in those who are at risk for these conditions. It has also been shown that the hypotension may lead to worse outcomes in hearing function in patients operated for vestibular schwannoma compared to those who do not develop the reflex.[18,31] In a prospective study of 100 patients after vestibular schwannoma surgery, Gharabaghi et al. found out that the occurrence of TCR was 11%.[18] With an overall hearing preservation of 47%, 11.1% of the patients in the TCR group and 51.4% of those in the nonTCR group, experienced preserved hearing function postoperatively.[18] In addition, in cases involving larger tumors, an intraoperative TCR was associated with a significantly worse postoperative hearing function during vestibular schwannoma surgery suggesting that the hypotension following TCR is—in addition to the tumor size—a negative prognostic factor for hearing preservation in patients undergoing VS surgery.[18] In another study, Schaller et al. compared the occurrence and persistence of tinnitus in patients with and without TCR.[32] Among 36 patients operated for vestibular schwannoma, TCR occurred in 17% and influenced the Figure 1: TCR: Management of trigemino-cardiac reflex

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manipulations of the trigeminal nerve. anticholinergics, atropine and/or glycopyrrolate IV may be used to partially prevent a TCR.[38] Hunsley et al. 3. Careful cardiovascular monitoring during anesthesia evaluated the efficacy of IV atropine and glycopyrrolate especially in those with risk factors for TCR. in the prevention of the OCR in children operated for 4. Treatment of the condition when it occurs: strabismus. They tested different doses of the two drugs, glycopyrrolate 5 and 7.5 mg/kg and atropine 10 and i. cessation of the manipulation, and; 15 mg/kg. Overall, there is a reduction in the rate of ii. administration of vagolytic agents or adrenaline. bradycardia to 23.8% to 33.3%.[39] But, they noticed that even higher doses of the two drugs, atropine 15 mg/kg The risk of TCR should be considered in any and glycopyrrolate 7.5 mg/kg i.v., given 5 min before neurosurgical intervention, especially at the skull base. induction of anesthesia, are not sufficient to protect If any mechanical stimulation to the trigeminal nerve completely against the OCR in children. is necessary, which is a rather “robust” nerve, should be as gentle as possible. If working in the vicinity of In a study done to evaluate the efficacy of IV or IM the nerve or its branches, the anesthesiologist should vagolytic agents (atropine and glycopyrrpolate), in be notified by the surgeon. Continuous intraoperative children undergoing squint surgery, Mirakhur et al. monitoring of hemodynamic parameters has been evaluated them in a controlled study and found out that shown to allow the surgeon to interrupt surgical the administration of the anticholinergic agents in both maneuvers immediately upon the occurrence of TCR. the IV and the IM forms may decrease the occurrence This technique has been proven sufficient in most cases of the OCR.[40] The overall frequency was approximately for the heart rate and the arterial blood pressure to return 40% (62 of 160 patients), but was 90% in those patients to normal levels without the necessity of additional who did not receive anticholinergic drugs.[40] The authors anticholinergic medication. Following this strategy, an concluded that, administration of anticholinergic drugs, uneventful further intraoperative and postoperative even by the IM route, decreased the frequency, and course may be achieved. However, the intraoperative glycopyrrolate 10 mg per kg being the most efficacious reaction of the surgeon to the TCR may be too late to by this route.[40] prevent postoperative neurological deficits under certain circumstances.[33,34] Intramuscular administration of anticholinergics has shown to be ineffective in preventing the TCR.[29,43] If controlled arterial hypotension is planned, the The use of atropine is, nowadays, questioned because prophylaxis of TCR is better accomplished with local cholinergic blockage reduces but does not totally prevent anesthetic infiltration or block of the nerve(s) which either bradycardia or hypotension in animals.[41] Another convey afferent stimuli. Shende et al. studied the efficacy reason is that, a trigeminal depressor response includes of peribulbar block with bupivacaine in patients operated both activation of vagal cardioinhibitory fibres and for retinal detachment.[35] They collected 60 patients who inhibition of adrenergic vasoconstriction as demonstrated were randomly assigned to receive either bupivacaine or after electrical stimulation of the spinal trigeminal tract IV morphine and studied the incidence and severity of and trigeminal nuclear complex. In addition, atropine the OCR. Apart from significantly reducing the incidence may cause serious cardiac arrhythmias itself, especially of OCR (30% vs. 70%), peribulbar bupivacaine also when halothane is the primary anaesthetic agent and attenuated the severity of the reflex.[35] Gupta et al. studied hence the dose must be carefully chosen.[42] the effect of peribulbar block in comparison to topical application of local anesthetic in children scheduled for Prabhakar et al. reported a 48-year-old female who strabismus surgery. They found out that the incidence developed severe bradycardia and hypotension during and severity of OCR intraoperatively was significantly craniotomy for parietal convexity meningioma; she was reduced in children who received a peribulbar block.[36] unresponsive to atropine and successfully managed Misurya et al. studied the effectiveness of prophylactic with epinephrine.[44] The action of adrenaline is to intravenous atropine sulphate which blocks the increase peripheral resistance via alpha-1 adrenoceptor peripheral muscarinic receptors at the heart and vasoconstriction, so that blood is shunted to the body’s retrobulbar xylocaine hydrochloride, which blocks core, and the alpha-1 adrenoceptor response which is to the conduction at ciliary ganglion on the afferent limb increase cardiac rate and output.[44] This important case of OCR. In this study, both atropine and retrobulbar report underscores the fact that TCR may be refractory xylocaine reduced the rate of OCR to 10-20%. But, when to atropine and other vagolytics and may rather need to both methods were used together, they were able to be managed with epinephrine.[44] completely suppress the OCR.[37] In general and with special reference to our case reported If there is no contraindication to intravenous here, the treatment of TCR deserves more attention. If

378 Neurology India | Jul-Aug 2009 | Vol 57 | Issue 4 Arasho, et al.: Trigeminocardiac reflex a TCR is elicited, the surgeon must stop the stimulus 11. Schaller BJ, Buchfelder M. Trigemino-cardiac reflex in skull base and wait until the pulse recovers its normal rhythm. surgery: From a better understanding to a better outcome? Acta Neurochir (Wien) 2006;148:1029-31. Occurrence of the TCR corresponds to the intensity of 12. Alexander JP. Reflex disturbances of cardiac rhythm during ophthalmic the mechanical stimulation on the trigeminal pathway. surgery. Br J Ophthalmol 1975;59:518-24. Abrupt and sustained traction is more likely to evoke 13. Loewinger J, Cohen M, Levi E. Bradycardia during elevation of a the TCR than smooth and gentle manipulations.[34,45-47] zygomatic arch fracture. J Oral Maxillofac Surg 1987;45:710-1. 14. Barnard NA, Bainton R. Bradycardia and the trigeminal nerve. J Craniomaxillofac Surg 1990;18:359-60. Conclusion 15. Roberts RS, Best JA, Shapiro RD. Trigeminocardiac reflex during temporomandibular joint arthroscopy: Report of a case. J Oral Maxillofac Surg 1999;57:854-6. In the present paper, we illustrated the clinical relevance 16. Shearer ES, Wenstone R. Bradycardia during elevation of zygomatic of the TCR and discussed its management. The most fractures. A variation of the oculocardiac reflex. Anaesthesia important aspects of management which were detailed 1987;42:1207-8. above are: (i) awareness of its possible occurrence in 17. Apt L, Isenberg S, Gaffney WL. The oculocardiac reflex in strabismus surgery. Am J Ophthalmol 1973;76:533-6. every patient undergoing head surgery (as there exist 18. Gharabaghi A, Koerbel A, Samii A, Kaminsky J, von Goesseln H, no identified risk factors); (ii) prophylactic peripheral Tatagiba M, et al. The impact of hypotension due to the trigeminocardiac nerve block in some type of surgeries (for example, reflex on auditory function in vestibular schwannoma surgery. strabismus surgery); (iii) avoidance of traction and J Neurosurg 2006;104:369-75. 19. Schaller B. Trigemino-cardiac reflex during transsphenoidal surgery gentle manipulation around the nerve, if any necessary for pituitary adenomas. Clin Neurol Neurosurg 2005; 107:468-474. intraoperatively; (iv) interaction between surgeon and 20. Schaller B. Trigeminocardiac reflex during microvascular trigeminal anethesiologists; (v) careful and continuous monitoring of decompression in cases of trigeminal neuralgia. J Neurosurg Anesthesiol the heart rate and blood pressure to detect its occurrence; 2005;17:45-8. 21. Filis A, Schaller B, Buchfelder M. Trigeminocardiac reflex in pituitary (vi) cessation of the mechanical stimulus upon recovery surgery. A prospective pilot study. 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block or topical application of local anesthesia combined with general 2007;1149:1169-75. anesthesia on intra-operative and postoperative complications during 43. Prabhakar H, Rath GP, Arora R. Sudden cardiac standstill during paediatric strabismus surgery. Anaesthesia 2007;62:1110-3. skin flap elevation in a patient undergoing craniotomy. J Neurosurg 37. Misurya VK, Singh SP, Kulshrestha VK. Prevention of oculocardiac Anesthesiol 2007;19:203-4. reflex (O.C.R) during extraocular muscle surgery. Indian J Ophthalmol 44. Prabhakar H, Ali Z, Rath GP. Trigemino-cardiac reflex may be 1990;38:85-7. refractory to conventional management in adults. Acta Neurochir (Wien) 38. Blanc VF. Trigeminocardiac reflexes. Can J Anesthesia 1991;38:696-9. 2008;150:509-10. 39. Hunsley E, Bush GH, Jones CJ. A study of Glycopyrrolate and Atropine 45. Schaller B, Filis A, Buchfelder M. Cardiac autonomic control in in the suppression of the oculocardiac reflex in strabismus surgery neurosurgery. Arch Med Sci 2007;4:287-92. in children. Br J Anaesth 1982;54:459-64. 46. Schaller B, Buchfelder M. Trigemino-cardiac reflex: A recently 40. Mirakhur RK, Jones CJ, Dundee JW, Archer DB. I.M or I.V atropine discovered “oxygen-conserving” response? The potential therapeutic or glycopyrrolate for the prevention of oculocardiac reflex in children role of a physiological reflex. Arch Med Sci 2006;2:3-5. undergoing squint surgery. Br J Anaesth 1982;54:1059. 41. Schaller B, Sandu N, Filis A, Buchfelder M. Peribulbar block of topical 47. Schaller B, Cornelius JF, Sandu N, Ottaviani G, Perez-Pinzon MA. application of local anesthesia combined for paediatric strabismus Oxygen-conserving reflexes of the brain: The current molecular surgery. Anaesthesia 2008;63:1142-3. knowledge. J Cell Mol Med 2009;13:644-7. 42. Schaller BJ, Weigel D, Filis A, Buchfelder M. Trigemino-cardiac reflex during transsphenoidal surgery for pituitary adenomas: Methodological Accepted on 24-07-09 description of a prospective skull base study protocol. Brain Res Source of Support: Nil, Conflict of Interest: None declared.

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